EP1753467A1

EP1753467A1 - Diagnostic agents for positron emission imaging using radiolabeled halogenated xanthenes and methods for positron emission imaging with radiolabeled halogenated xanthene diagnostic agents

Info

Publication number: EP1753467A1
Application number: EP05782465A
Authority: EP
Inventors: Timothy C. Scott; Craig H. Dees; Eric A. Wachter
Original assignee: Xantech Pharmaceuticals Inc
Current assignee: Provectus Pharmatech Inc
Priority date: 2004-06-10
Filing date: 2005-05-13
Publication date: 2007-02-21
Anticipated expiration: 2025-05-13
Also published as: EP1753467A4; WO2006001925A1; CA2570687A1; CA2570687C; JP2008502717A; MXPA06014266A; ES2398962T3; EP1753467B1

Abstract

New diagnostic agents for positron emission tomography (PET) and methods for use of such agents for imaging of human or animal tissue are described, wherein a primary active component of such agents is a radiolabeled halogenated xanthene or halogenated xanthene derivative. Preferably, the radiolabeled halogenated xanthene is radiolabeled Rose Bengal or a functional derivative of Rose Bengal.

Description

DIAGNOSTIC AGENTS FOR POSITRON EMISSION IMAGING USING RADIOLABELED HALOGENATED XANTHENES AND METHODS FOR POSITRON EMISSION IMAGING WITH RADIOLABELED HALOGENATED XANTHENE DIAGNOSTIC AGENTS BACKGROUND OF THE INVENTION [0001] The present invention is directed to new diagnostic agents, and methods of use of such agents, for medical imaging using positron emission tomography (PET). PET is a nuclear medicine imaging technique which produces a three dimensional image of the body. PET imaging is commonly used to obtain non-invasive information about internal body structures and tissues and the function and health of such structures and tissues. PET uses a metabolically active molecule and a short-lived radioactive tracer isotope (to radiolabel the active molecule) as a diagnostic agent. The isotope decays by emitting a positron. When a PET diagnostic agent is administered to the body, it is retained or accumulates in certain tissues of interest, thereby facilitating imaging of those tissues based upon detection of gamma ray photons produced upon annihilation of positrons emitted from the radiolabeled PET diagnostic agent. Such annihilation occurs when an emitted positron collides with an electron present in the vicinity of emission, resulting in production of two 511 keV photons that are emitted in nearly opposite directions. Typically, such PET diagnostic agents are radiolabeled with (i.e., contain) one or more atoms that exhibit positron emission (such as certain isotopes of carbon, nitrogen, oxygen, fluorine, or rubidium, including ¹¹C, ¹³N, ¹⁵0, ¹⁸F, and ⁸²Rb). The effects of the emitted positrons (i.e., the subsequently emitted gamma ray photons) are detected by a detection device located outside the body which typically converts raw data into two- or three- dimensional images of the region of interest. The results are then read by a nuclear medicine physician or radiologist to interpret the results in terms of the patient's diagnosis and treatment. [0002] Considerable effort has been invested in development of PET diagnostic agents in an effort to improve contrast between various anatomical features, such as between cancerous and non¬ cancerous tissues. Continued progress in medical science mandates improved options in such diagnostic capability, which in turn mandates further development of improved diagnostic agents. [0003] Therefore, it is one object of the present invention to meet these characteristics, to overcome the drawbacks in prior methods and agents and to provide an improvement over these prior methods and agents.

SUMMARY OF THE INVENTION [0004] The present invention is directed to certain diagnostic agents for PET imaging and methods for using such agents exhibiting positron emission. [0005] hi a preferred embodiment, a primary component of such diagnostic agent is a halogenated xanthene or a functional derivative of a halogenated xanthene that has been radiolabeled with one or more positron emitting isotopes of carbon, oxygen, fluorine, chlorine, bromine, or iodine, including ¹⁰C, ¹¹C, ¹³0, ¹⁴0, ¹⁵0, ¹⁷F, ¹⁸F, ³²Cl, ³³Cl, ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷I₅ ¹¹⁸1, ¹¹⁹1, ¹²⁰I, ¹²¹1, ¹²²1, ¹²⁴1, ¹²⁶I, and ¹²⁸I. hi a further preferred embodiment, this radiolabeled halogenated xanthene is Rose Bengal or a functional derivative of Rose Bengal. [0006] These invented agents can be used in a method for imaging human or animal tissue comprising the steps of: administering a diagnostic agent to a patient, a portion of said diagnostic agent being retained in tissue of interest, said diagnostic agent emitting positrons; and imaging said tissue based on the effects of said positrons emitted from the diagnostic agent, wherein said diagnostic agent is a radiolabeled halogenated xanthene. BRIEF DESCRIPTION OF THE DRAWINGS [0007] FIGURE Ia is an illustration of the chemical structure of a halogenated xanthene; and [0008] FIGURE Ib is an illustration of the chemical structure of Rose Bengal.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENT [0009] The present invention is directed to certain diagnostic agents for PET imaging and methods for using such agents exhibiting positron emission, hi a preferred embodiment, a primary component of such diagnostic agent is a halogenated xanthene or a functional derivative of a halogenated xanthene that has been radiolabeled with one or more positron emitting isotopes of carbon, oxygen, fluorine, chlorine, bromine, or iodine, including ¹⁰C, ¹¹C, ¹³0, ¹⁴0, ¹⁵O₅ ¹⁷F, ¹⁸F₅ ³²Cl, ³³Cl, ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷1, ¹¹⁸1, ¹¹⁹1, ¹²⁰1, ¹²¹1, ¹²²1, ¹²⁴1, ¹²⁶I, and ¹²⁸I. In a further preferred embodiment, this radiolabeled halogenated xanthene is Rose Bengal (i.e., 4,5,6,7-tetrachloro- 2',4',5',7'-tetraiodofluorescein) or a functional derivative of Rose Bengal. [00010] The halogenated xanthenes constitute a family of extremely useful agents that can be selectively and safely delivered at high concentrations to certain tissues. Certain properties of the halogenated xanthenes are described in US SN 09/184,388, filed on November 2, 1998, in US SN 09/216,787, filed on December 21, 1998, in USSN 09/635,276, filed on August 9, 2000, in USSN 09/799,785, filed on March 6, 2001, in USSN 09/817,448, filed on March 26, 2001, in USSN 09/900,355, filed on July 6, 2001, and in USSN 10/314,840, filed on December 9, 2002, which are herein incorporated by reference in their entirety. In general, the halogenated xanthenes are characterized by a low cytotoxicity (toxicity to cells) at low concentration, a propensity for selective concentration or retention in certain tissues and cells, a high cytotoxicity upon such concentration or retention, and by chemical and physical properties that are substantially unaffected by the local chemical environment or by the attachment of functional derivatives at positions R¹ and R² described below. [00011] The generalized chemical structure of the halogenated xanthenes is illustrated in Figure Ia, where the symbols X, Y, and Z represent various elements present at the designated positions, and the symbols R¹ and R² represent various functionalities present at the designated positions. The chemical structure of a specific example of a halogenated xanthene, Rose Bengal, is illustrated in Figure Ib. Physical properties of representative halogenated xanthenes are summarized in attached Table 1. Li general, the halogenated xanthenes have the empirical formula, C₂₀H_nO₅F₃CI_bBr₀I_(J5R¹, R², where n >2, and a, b, c, and d are integers greater than or equal to zero. For example, the empirical formula for the disodium salt of Rose Bengal is C₂₀H₂O₅F₀Cl₄Br₀I₄₅R¹ _JR², where R¹ and R² each represent a sodium atom, or, more simply, C₂₀H₂O₅Cl₄I₄₅Na₂. [00012] hi their non-radiolabeled form, the halogenated xanthenes are useful as food dyes, biological stains, photosensitizers (i.e. agents which are used with light for photodynamic imaging or treatment as for example disclosed in USSN 09/635,276 and 09/799,785), radiosensitizers (i.e., agents that are used with applied ionizing radiation for imaging and radiation treatment as for example disclosed in USSN 09/216,787 and 09/817,448), and as chemoablative or chemotherapeutic agents (as for example disclosed in USSN 09/900,355). When labeled with certain gamma-emitting isotopes of iodine (i.e., ¹³¹I and ¹²⁵I), one of the halogenated xanthenes (Rose Bengal) has proven useful for diagnosis of hepatic function based on either measurement of differential excretion or imaging of the pattern of gamma emission from such radiolabeled molecules (for example as disclosed in Serafmi et al.₅ J. Nucl. Med. 16 (1975) 629-633). [00013] The present inventors were part of a team that has previously discovered and disclosed that the halogenated xanthenes exhibit selective retention in certain types of tissue, especially those exhibiting cancerous or precancerous conditions (i.e., neoplasia, dysplasia, and hyperplasia), as disclosed in USSN 09/635,276, 09/799,785, 09/216,787, 09/817,448, and 09/900,355. Such retention can be useful for diagnosis (for example, using x-ray computed tomography or ultrasound imaging) and for therapy (for example, using photodynamic therapy or radiosensitization). [00014] The present inventors have now discovered new isotopically-labeled (i.e., radiolabeled) members of the halogenated xanthene family that are capable of serving as diagnostic agents for PET imaging. More specifically, Applicants have created new halogenated xanthene compounds wherein a halogenated xanthene or a functional derivative of a halogenated xanthene has been radiolabeled with one or more positron emitting isotope of carbon, oxygen, fluorine, chlorine, bromine, or iodine, including ¹⁰C, ¹¹C, ¹³0, ¹⁴0, ¹⁵0, ¹⁷F, ¹⁸F, ³²Cl, ³³Cl₅ ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷I, ¹¹⁸I, ¹¹⁹I, ¹²⁰I₅ ¹²¹I, ¹²²I, ¹²⁴I₅ ¹²⁶I, and ¹²⁸I. One skilled in the art can synthesize and produce these new compounds using known chemistry of the halogenated xanthenes with the additional information provided in this application. For example, the synthesis and production of non-radiolabeled halogenated xanthenes and the chemistry of such compounds is known. Labeling with radioisotopes, such as for example the preferred radioisotopes of bromine or iodine (i.e., ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷I₅ ¹¹⁸1, ¹¹⁹I₅ ¹²⁰1, ¹²¹1, ¹²²1, ¹²⁴1, ¹²⁶I, and ¹²⁸I), can be achieved by using standard halogen exchange methods, such as those taught in Serafmi, supra. For these radioisotopes and the other radioisotopes listed herein, radiolabeling can be achieved using radiolabeled starting materials in the synthesis of the desired halogenated xanthene (such as for example radiolabeled resorcinol or a radiolabeled phthalic anhydride), thereby directly synthesizing the radiolabeled xanthene. [00015] The present inventors have further discovered that a halogenated xanthene or a functional derivative of a halogenated xanthene that has been radiolabeled with one or more positron emitting isotope of carbon, oxygen, fluorine, chlorine, bromine, or iodine, including ¹⁰C, ¹¹C₅ ¹³O, ¹⁴O₅ ¹⁵0, ¹⁷F, ¹⁸F₅ ³²Cl, ³³Cl, ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br₅ ⁷⁷Br, ⁷⁸Br, ¹¹⁷1, ¹¹⁸I₅ ¹¹⁹I₅ ¹²⁰1, ¹²¹I₅ ¹²²I₅ ¹²⁴1, ¹²⁶I, and ¹²⁸I, can be useful as the active substance in a diagnostic agent for PET imaging. This non-naturally- occuπing, novel composition of matter will retain the desirable specificity, toxicity, and other salient pharmaceutical properties of the halogenated xanthenes, as discussed above. Some of the important physical properties of the preferred positron emitting isotopes of carbon, oxygen, fluorine, chlorine, bromine, and iodine are summarized in attached Table 2. Because positron emitting isotopes with very short half-lives may in general be impractical for use in diagnostic procedures due to logistic difficulties in their timely production and subsequent delivery to the patient, those isotopes exhibiting half-lives in excess of approximately one minute are preferred and are more useful. These preferred longer-lived positron emitting isotopes include ¹¹C, ¹⁵O, ¹⁸F, ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷I₅ ¹¹⁸I, ¹¹⁹I, ¹²⁰I, ¹²¹I₅ ¹²²I₅ ¹²⁴I₅ ¹²⁶I₅ and ¹²⁸I. Because the distance traveled by the emitted positron prior to annihilation adversely affects image resolution (where traveled distance is proportional to positron energy), those longer-lived isotopes emitting lower energies are more preferred. Hence, the more preferred longer-lived, lower-energy positron emitting isotopes include ¹¹C, ¹⁸F, ⁷⁵Br, ⁷⁷Br, ¹²¹1, ¹²⁴I, and ¹²⁶I. [00016] Thus, a diagnostic agent containing a halogenated xanthene radiolabeled with one or more of the aforementioned positron emitting elements can be used as a diagnostic agent for PET. [00017] Hence, one preferred embodiment of the present invention is a diagnostic agent that contains, as an active ingredient at a concentration of from greater than approximately 0.001% to less than approximately 20%, at least one halogenated xanthene radiolabeled with one or more positron emitting isotope selected from the group of ¹⁰C, ¹¹C, ¹³0, ¹⁴O₅ ¹⁵0, ¹⁷F, ¹⁸F, ³²Cl, ³³Cl, ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br₅ ⁷⁸Br₅ ¹¹⁷1, ¹¹⁸1, ¹¹⁹I₅ ¹²⁰I₅ ¹²¹1, ¹²²1, ¹²⁴1, ¹²⁶I, and ¹²⁸I (i.e., a radiolabeled halogenated xanthene). It is further preferred that this radiolabeled halogenated xanthene is radiolabeled with one or more longer-lived positron isotope selected from the group of ¹¹C, ¹⁵0, ¹⁸F, ³⁴Cl₅ ⁷⁴Br₅ ⁷⁵Br₅ ⁷⁶Br, ⁷⁷Br, ⁷⁸Br₅ ¹¹⁷I₅ ¹¹⁸I₅ ¹¹⁹I₅ ¹²⁰I₅ ¹²¹I, ¹²²I₅ ¹²⁴I, ¹²⁶I₅ and ¹²⁸I. It is further preferred that this radiolabeled halogenated xanthene is radiolabeled with one or more longer-lived, lower-energy positron emitting isotopes selected from the group of ¹¹C, ¹⁸F, ⁷⁵Br, ⁷⁷Br, ¹²¹1, ¹²⁴I, and ¹²⁶I. [00018] It is further preferred that this radiolabeled halogenated xanthene is radiolabeled Rose Bengal. [00019] Examples of radiolabled halogenated xanthenes which can be used in the diagnostic agent of the present invention include one or more of the following: radiolabeled 4',5'-Dichlorofluorescein; radiolabeled 2',7'-Dichlorofluorescein; radiolabeled 4,5 ,6,7-Tetracrύorofmorescein; radiolabeled 2',4^I,5',7'-Tetrachlorofluorescein; radiolabeled Dibromofluorescein; radiolabeled Solvent Red 72; radiolabeled Diiodofluorescein; radiolabeled Eosin B; radiolabeled Eosin Y; radiolabeled Ethyl Eosin; radiolabeled Erythrosin B; radiolabeled Phloxine B; radiolabeled Rose Bengal; radiolabeled 4,5,6,7-Tetrabromoerythrosin; radiolabeled Mono-, Di-, or Tribromoerythrosin; radiolabeled Mono-, Di-, or Trichloroerythrosin; radiolabeled Mono-, Di-, or Trifluoroerythrosin; radiolabeled 2'₅7'-Dichloro-4,5,6,7-Tetrafluorofluorescein; radiolabeled 2',4,5,6,7,7'-Hexafluorofluorescein; radiolabeled 4,5 ,6,7-Tetrafluorofluorescein, radiolabeled 2',4',5,5',6,7'-Hexaiodofluorescein; radiolabeled 2',4',5,5',7,7'-Hexaiodofluorescein; radiolabeled 2',4',5',6,7,7'-Hexaiodofluorescein; radiolabeled 2',4',5,5',6,7,7'-Heptaiodofluorescein; radiolabeled 4-Chloro-2',4',5,5',6,7'-hexaiodofluorescein; radiolabeled 4-Chloro-2',4',5,5',7,7'-hexaiodofluorescein; radiolabeled 4-Chloro-2^l,4',5',6,7,7'-hexaiodofluorescein; radiolabeled 4-Chloro-2'₅4',5,5'₅6,7,7^t-heptaiodofluorescein; radiolabeled 4,5-Dichloro-2^l,4',5^l,6,7,7'-hexaiodofluorescein; radiolabeled 4,6-Dichloro-2',4',5₅5^l,7,7'-hexaiodofluorescein; and radiolabeled 4, 7-Dichloro-2',4',5,5',6,7'-hexaiodofluorescein, wherein said radiolabel comprises incorporation of one or more positron emitting isotope selected from the group of ¹⁰C, ¹¹C₅ ¹³0, ¹⁴O₅ ¹⁵0, ¹⁷F₅ ¹⁸F, ³²Cl, ³³Cl₅ ³⁴Cl₃ ⁷⁴Br₅ ⁷⁵Br₅ ⁷⁶Br₅ ⁷⁷Br₅ ⁷⁸Br₅ ¹¹⁷I₅ ¹¹⁸I₅ ¹¹⁹I₅ ¹²⁰I₅ ¹²¹I₅ ¹²²I₅ ¹²⁴I₅ ¹²⁶I₅ and ¹²⁸I. [00020] In an alternate preferred embodiment, positron emission tomography is used to image, detect or otherwise observe the presence of a diagnostic agent that contains, at a concentration of from greater than approximately 0.001% to less than approximately 20%, at least one radiolabeled halogenated xanthene. It is further preferred that this diagnostic agent include the radiolabeled form of the halogenated xanthene Rose Bengal. [00021] This description has been offered for illustrative purposes only and is not intended to limit the invention of this application. [00022] Table 1. Physical properties of some example halogenated xanthenes (non- radiolabeled). [00023] Table 2. Isotopes of relevance for PET with the halogenated xanthenes. [00024] What is claimed as new and desired to be protected by Letters Patent is set forth in the appended claims.

Claims

We claim: 1. A diagnostic agent comprising at least one positron emitting radiolabeled halogenated xanthene as a primary active component, wherein said agent is useful for positron emission imaging of human and animal tissue. 2. The diagnostic agent of Claim 1 wherein said radiolabeled halogenated xanthene is selected from the group consisting of radiolabeled 4'₅5'-Dichlorofluorescein, radiolabeled 2',7'- Dichlorofluorescein, radiolabeled 4,5,6,7-Tetrachlorofluorescein, radiolabeled 2',4',5',7'- Tetrachlorofiuorescein, radiolabeled Dibromofluorescein, radiolabeled Solvent Red 72, radiolabeled Diiodofluorescein, radiolabeled Eosin B, radiolabeled Eosin Y, radiolabeled Ethyl Eosin, radiolabeled Erythrosin B, radiolabeled Phloxine B, radiolabeled Rose Bengal, radiolabeled 4,5,6,7- Tetrabromoerythrosin, radiolabeled Mono-, Di-, or Tribromoerythrosin, radiolabeled Mono-, Di-, or Trichloroerythrosin, radiolabeled Mono-, Di-, or Trifluoroerythrosin, radiolabeled 2',7'-Dichloro- 4,5,6,7-Tetrafluorofluorescein, radiolabeled 2',4,5,6,7,7'-Hexafluorofluorescein, radiolabeled 4,5,6,7- Tetrafluorofluorescein, radiolabeled 2',4',5,5',6,7'-Hexaiodofluorescein, radiolabeled 2',4',5,5',7,7'- Hexaiodofluorescein, radiolabeled 2',4',5',6,7,7'-Hexaiodofluorescein, radiolabeled 2',4',5,5',6,7,7'- Heptaiodofluorescein, radiolabeled 4-Chloro-2',4',5,5',6,7'-hexaiodofiuorescein, radiolabeled 4- Chloro-2^I,4',5,5',7,7'-hexaiodofluorescein, radiolabeled 4-Chloro-2',4',5^I,6,7,7'-hexaiodofluorescein, radiolabeled 4-Chloro-2',4',5,5',6,7,7'-heρtaiodofluorescein, radiolabeled 4,5-Dichloro-2',4',5',6,7,7'- hexaiodofluorescein, radiolabeled 4,6-Dichloro-2^l,4',5,5',7,7'-hexaiodofluorescein, and radiolabeled 4,7-Dichloro-2',4^I,5,5',6,7'-hexaiodofluorescein. 3. The diagnostic agent of Claim 1 wherein said radiolabel comprises incorporation, into said halogenated xanthene, of one or more positron emitting isotope selected from the group consisting Of ¹⁰C, ¹¹C, ¹³0, ¹⁴0, ¹⁵0, ¹⁷F, ¹⁸F, ³²Cl, ³³Cl, ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷1, ¹¹⁸1, ¹¹⁹1, ¹²⁰1, ¹²¹1, ¹²²I, ¹²⁴1, ¹²⁶I, and ¹²⁸I. 4. The diagnostic agent of Claim 1 wherein said radiolabeled halogenated xanthene is present in a concentration of greater than about 0.001% to less than about 20%. 5. A diagnostic agent comprising at least one halogenated xanthene as a primary active component, wherein said halogenated xanthene has been radiolabeled with at least one positron emitting isotope selected from the group of elements consisting of carbon, oxygen, fluorine, chlorine, bromine, and iodine. 6. The diagnostic agent of Claim 5 wherein said positron emitting isotope is selected from the group consisting of ¹⁰C, ¹¹C, ¹³0, ¹⁴0, ¹⁵0, ¹⁷F, ¹⁸F, ³²Cl, ³³Cl, ³⁴Cl, ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷I, ¹¹⁸1, ¹¹⁹1, ¹²⁰1, ¹²¹1, ¹²²I₅ ¹²⁴1, ¹²⁶I, and ¹²⁸I. 7. The agent of Claim 5 wherein said halogenated xanthene is present in a concentration of greater than about 0.001% to less than about 20%. 8.A diagnostic agent comprising at least one positron emitting radiolabeled halogenated xanthene as a primary active component, wherein said radiolabeled halogenated xanthene is Rose Bengal or a functional derivative of Rose Bengal. 9. The agent of Claim 8 wherein said radiolabled halogenated xanthene is present in a concentration of greater than about 0.001% to less than about 20%. 10. A positron emitting halogenated xanthene, wherein said halogenated xanthene has been radiolabeled with at least one positron emitting isotope selected from the group consisting of ¹⁰C₅ ¹¹C, ¹³0, ¹⁴0, ¹⁵0, ¹⁷F, ¹⁸F, ³²Cl, ³³Cl, ³⁴Cl₅ ⁷⁴Br₅ ⁷⁵Br₅ ⁷⁶Br₅ ⁷⁷Br₅ ⁷⁸Br, ¹¹⁷I₅ ¹¹⁸I₅ ¹¹⁹1, ¹²⁰1, ¹²¹I₅ ¹²²I₅ ¹²⁴I₅ ¹²⁶I₅ and ¹²⁸I. 11. A method for imaging human or animal tissue comprising the steps of: administering a diagnostic agent to a patient, a portion of said diagnostic agent being retained in tissue of interest, said diagnostic agent emitting positrons; and imaging said tissue based on the effects of said positrons emitted from the diagnostic agent, wherein said diagnostic agent comprises a positron emitting radiolabeled halogenated xanthene. 12. The method of Claim 11 wherein said radiolabeled halogenated xanthene is present in a concentration of greater than about 0.001% to less than about 20%. 13. The method of Claim 11 wherein said radiolabeled halogenated xanthene is radiolabeled Rose Bengal. 14. The method of Claim 11 wherein said radiolabeled halogenated xanthene is selected from the group consisting of radiolabeled 4',5'-Dichlorofluorescein, radiolabeled 2',7'-Dichlorofluorescein, radiolabeled 4,5,6,7-Tetrachlorofluorescein, radiolabeled 2',4^I,5',7^I-Tetrachlorofluorescein, radiolabeled Dibromofluorescein, radiolabeled Solvent Red 72, radiolabeled Diiodofluorescein, radiolabeled Eosin B, radiolabeled Eosin Y, radiolabeled Ethyl Eosin, radiolabeled Erythrosin B, radiolabeled Phloxine B, radiolabeled 4,5,6,7-Tetrabromoerythrosin, radiolabeled Mono-, Di-, or Tribromoerythrosin, radiolabeled Mono-, Di-, or Trichloroerythrosin, radiolabeled Mono-, Di-, or Trifluoroerythrosin, radiolabeled 2^l,7'-Dichloro-4,5,6,7-Tetrafluorofluorescein, radiolabeled 2',4,5,6,7,7'-Hexafluorofluorescein, radiolabeled 4,5,6,7-Tetrafluorofluorescein, radiolabeled 2',4^I,5,5',6,7'-Hexaiodofluorescein, radiolabeled 2',4',5,5',7,7'-Hexaiodofluorescein, radiolabeled 2^t,4',5',6,7,7^l-Hexaiodofluorescein,radiolabeled2^I,4',5,5',6₅7,7^l-Heptaiodofluorescein, radiolabeled 4-Chloro-2^l,4^I,5,5',6,7'-hexaiodofluorescein, radiolabeled 4-Chloro-2',4',5,5',7,7'- hexaiodofluorescein, radiolabeled 4-Chloro-2',4',5',6,7,7'-hexaiodofluorescein, radiolabeled 4- Chloro^'^'^^'^^^'-heptaiodofluorescein, radiolabeled 4,5-Dichloro-2',4',5',6,7,7'- hexaiodofluorescein, radiolabeled 4,6-Dichloro-2^I,4',5,5',7,7'-hexaiodofluorescein, and radiolabeled 4,7-Dichloro-2^t ₅4^l,5,5',6,7'-hexaiodofluorescein. 15. The method of Claim 11 wherein said radiolabel comprises incorporation, into said haiogenated xanthene, of one or more positron emitting isotope selected from the group consisting Of ¹⁰C, ¹¹C, ¹³0, ¹⁴0, ¹⁵0, ¹⁷F, ¹⁸F, ³²Cl, ³³Cl, ³⁴Cl₅ ⁷⁴Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁸Br, ¹¹⁷1, ¹¹⁸1, ¹¹⁹1, ¹²⁰1, ¹²¹I₅ ¹²²I₅ ¹²⁴1, ¹²⁶I₅ and ¹²⁸I.